Quinoxalinyl/quinoxaliy; alkyl-N-terminal amino hydroxy

ABSTRACT

Non-peptidyl compounds characterized generally as quinoxalinyl/qunioxalinylalkyl-N-terminal amino hydroxy β-amino acid derivatives are useful as renin inhibitors for treatment of hypertension. Compounds of particular interest are of the formula ##STR1## wherein R 1  is selected from ##STR2## wherein each of Y and Z is independently selected from hydrido, chloro, fluoro, methoxy and dimethylamino; wherein n is a number selected from zero through four, inclusive; wherein each of R 2  and R 4  is independently selected from hydrido and methyl; wherein R 3  is methyl or ethyl; wherein R 5  is cyclohexylmethyl; wherein R 6  is hydroxy; and wherein R 7  is isobutyl or ethyl; or a pharmaceutically-acceptable salt thereof.

This is a divisional of application Ser. No. 07/445,257 filed Dec. 4,1989 now abandoned.

FIELD OF THE INVENTION

Renin-inhibiting compounds are known for control of hypertension. Ofparticular interest herein are non-peptidyl compounds useful as renininhibiting agents.

BACKGROUND OF THE INVENTION

Renin is a proteolytic enzyme produced and secreted into the bloodstreamby the juxtaglomerular cells of the kidney. In the bloodstream, renincleaves a peptide bond in the serum protein angiotensinogen to produce adecapeptide known as angiotensin I. A second enzyme known as angiotensinconverting enzyme, cleaves angiotensin I to produce the octapeptideknown as angiotensin II. Angiotensin II is a potent pressor agentresponsible for vasoconstriction and elevation of cardiovascularpressure. Attempts have been made to control hypertension by blockingthe action of renin or by blocking the formation of angiotensin II inthe body with inhibitors of angiotensin I converting enzyme.

Classes of compounds published as inhibitors of the action of renin onangiotensinogen include renin antibodies, pepstatin and its analogs,phospholipids, angiotensinogen analogs, pro-renin related analogs andpeptide aldehydes.

A peptide isolated from actinomyces has been reported as an inhibitor ofaspartyl proteases such as pepsin, cathepsin D and renin [Umezawa et al,in J. Antibiot. (Tokyo), 23, 259-262 (1970)]. This peptide, known aspepstatin, was found to reduce blood pressure in vivo after theinjection of hog renin into nephrectomized rats [Gross et al, Science,175, 656 (1971)]. Pepstatin has the disadvantages of low solubility andof inhibiting acid proteases in addition to renin. Modified pepstatinshave been synthesized in an attempt to increase the specificity forhuman renin over other physiologically important enzymes. While somedegree of specificity has been achieved, this approach has led to ratherhigh molecular weight hepta- and octapeptides [Boger et al, Nature, 303,81 (1983)]; high molecular weight peptides are generally consideredundesirable as drugs because gastrointestinal absorption is impaired andplasma stability is compromised.

Short peptide aldehydes have been reported as renin inhibitors [Kokubuet al. Biochim. Biophys. Res. Commun., 118, 929 (1984); Castro et al.FEBS Lett., 167, 273 (1984)]. Such compounds have a reactive C-terminalaldehyde group and would likely be unstable in vivo.

Other peptidyl compounds have been described as renin inhibitors. EPAppl. #128,762, published Dec. 18, 1984, describes dipeptide andtripeptide glycol-containing compounds as renin inhibitors [also seeHanson et al. Biochim. Biophys. Res. Commun., 132, 155-161 (1985), 146,959-963 (1987)]. EP Appl. #181,110, published May 14, 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #189,203,published Jul. 30, 1986, describesalkylnaphthyl-methylpropionyl-histidyl aminohydroxy alkanoates as renininhibitors. EP Appl. #216,539, published Apr. 1, 1987, describesalkylnaphthylmethylpropionyl aminoacyl aminoalkanoate compounds as renininhibitors orally administered for treatment of renin-associatedhypertension. EP Appl. #229,667 published Jul. 22, 1987 describes acyla-aminoacyl aminodiol compounds having a piperazinylcarbonyl or analkylaminoalkylcarbonyl terminal group at the N-amino acid terminus,such as 2(S)-{[(1-piperazinyl)carbonyl-oxy]-3-phenylpropionyl}-Phe-Hisamide of 2(S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methylheptane.PCT Application No. WO 87/04349 published Jul. 30, 1987 describesaminocarbonyl aminoacyl hydroxyether derivatives having analkylamino-containing terminal substituent and which are described ashaving renin-inhibiting activity for use in treating hypertension. EPAppl. #300,189 published Jan. 25, 1989 describes amino acid monohydricderivatives having an alkylamino-alkylamino N-terminus which arementioned as useful in treating hypertension. EP Appl. #266,950published Nov. 5, 1988 describes heterocycliccarbonyl amino acidderivatives which are mentioned as having renin-inhibiting activity foruse in treating hypertension.

DESCRIPTION OF THE INVENTION

Heterocyclic acyl aminodiol β-amino acid derivatives having utility asrenin inhibitors for treatment of hypertension in mammals constitute afamily of compounds of general Formula I: ##STR3## wherein R₁ isselected from aryl, aralkyl, heteroaryl and heteroaralkyl; wherein eachof R₂ and R₄ is independently selected from hydrido and lower alkyl;wherein R₃ is selected from hydrido, alkyl, benzyl, cycloalkyl,cycloalkylalkyl, alkoxyalkyl, alkylthioalkyl and imidazolemethyl;wherein R₅ is selected from cycloalkyl, phenyl, lower alkyl,cycloalkylalkyl and phenylalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino, dialkylamino, lower alkyl andcycloalkyl; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may be taken together to form a carbocyclic orheterocyclic ring consisting of from 3 to about 8 ring members, whichheterocyclic ring contains a hetero ring atom selected from oxygen atom,sulfur atom and NH; wherein each of R₈ and R₉ is independently selectedfrom hydrido, alkyl, phenyalkyl, cycloalkyl, heterocyclicalkyl andphenyl; wherein R₈ and R₉ may be taken together to form a carbocyclic orheterocyclic ring consisting of from three to about eight ring members,which heterocyclic ring contains a hetero ring atom selected from oxygenatom, sulfur atom and ##STR4## and wherein any of the foregoing R₁through R₉ substituents having a substitutable position may besubstituted with one or more groups selected from alkyl, alkoxy, halo,haloalkyl, alkenyl, alkynyl and cyano; or a pharmaceutically-acceptablesalt thereof.

A preferred family of compounds consists of those compounds of Formula Iwherein R₁ is selected from aryl and aralkyl groups represented by##STR5## and wherein R₁ may be further selected from heteroaryl andheteroaralkyl represented by ##STR6## wherein X is selected from O, S,alkylamino and NH; wherein each of Y and Z is independently selectedfrom lower alkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino,dialkylamino, aryl, sulfhydryl and thioalkyl; wherein Q is selected fromO and S; wherein each of T and A is independently selected from N andCH; wherein n is a number selected from zero through five, inclusive;wherein each of R₂ and R₄ is independently selected from hydrido andlower alkyl; wherein R₃ is selected from hydrido, alkyl, alkoxyalkyl,alkylthioalkyl and imidazolemethyl; wherein R₅ is selected fromsubstituted or unsubstituted lower alkyl, cycloalkylalkyl andphenylalkyl; wherein R₆ is selected from hydrido, hydroxy, alkoxy,amino, alkylamino and dialkylamino; wherein R₇ is selected from hydrido,alkyl, haloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyland alkoxycarbonyl; wherein R₆ and R₇ may be taken together to form acarbocyclic or heterocyclic ring consisting of from 3 to about 6members, which heterocyclic ring contains a hetero ring atom selectedfrom oxygen atom, sulfur atom and NH; wherein each of R₈ and R₉ isindependently selected from hydrido, alkyl, phenylalkyl, cycloalkyl,heterocyclicalkyl and phenyl; wherein R₈ and R₉ may be taken together toform a carbocyclic or heterocyclic ring consisting of from three toabout six members, which heterocyclic ring contains a hetero ring atomselected from oxygen atom, sulfur atom and ##STR7## and wherein any ofthe foregoing R¹ through R⁹ substituents may be substituted with one ormore groups selected from alkyl, alkoxy, halo, haloalkyl, alkenyl,alkynyl and cyano; or a pharmaceutically-acceptable salt thereof.

A further preferred family of compounds consists of those compounds ofFormula I wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from hydrido, methyl, ethyl,methoxymethyl, methylthiomethyl and imidazolemethyl; wherein R₅ isselected from benzyl, cyclohexylmethyl, isobutyl and n-butyl; wherein R₆is selected from hydrido, hydroxy, methoxy and dialkylamino; wherein R₇is selected from isobutyl, ethyl, propyl and benzyl; wherein R₆ and R₇may be taken together to form a carbocyclic or heterocyclic ringconsisting of from 3 to about 6 members, which heterocyclic ringcontains a hetero ring atom selected from oxygen atom, sulfur atom and##STR8## wherein each of R₈ and R₉ is independently selected hydrido,methyl, isopropyl, isobutyl, benzyl and imidazolemethyl; wherein R₈ andR₉ may be taken together to form a ring consisting of from three toabout six members, which heterocyclic ring contains a hetero ring atomselected from oxygen atom, sulfur atom and ##STR9## wherein X isselected from alkylamino, NH, oxygen atom and sulfur atom; wherein eachof Y and Z is independently selected from lower alkyl, hydroxy, halo,alkoxy, amino, alkylamino, dialkylamino, aryl, sulfhydryl and thioalkyl;wherein Q is oxygen atom; wherein each of T and A is independentlyselected from N and CH; wherein n is a number selected from zero throughfour.

A more preferred family of compounds consists of those compounds ofFormula I wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from methyl and ethyl;wherein R₅ is cyclohexylmethyl; wherein R₆ is hydroxy; wherein R₇ isselected from isobutyl and ethyl; wherein each of R₈ and R₉ isindependently selected from hydrido, methyl and isopropyl; wherein X isselected from oxygen atom, methylamino ##STR10## wherein each of Y and Zis independently selected from Cl, F, methoxy and dimethylamino; whereinQ is oxygen atom; wherein each of T and A is independently selected fromN and CH; wherein n is a number selected from zero through four.

The term "hydrido" denotes a single hydrogen atom (H) which may beattached, for example, to a carbon atom to form hydrocarbyl ormethylene, for example, or attached to an oxygen atom to form a hydroxylgroup. Where the term "alkyl" is used, either alone or within otherterms such as "haloalkyl", "aralkyl" and "hydroxyalkyl", the term"alkyl" embraces linear or branched radicals having one to about twentycarbon atoms. Preferred alkyl radicals are "lower alkyl" radicals havingone to about ten carbon atoms. Examples of which include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, 1-methylhexyl, n-heptyl, 2-ethylheptyl,n-octyl, 3-propyloctyl, n-nonyl, 4-butylnonyl, n-decyl and the like. Theterm "cycloalkyl", embraces radicals having three to ten carbon atoms,such as cyclopropyl and cyclobutyl. "Alkylcycloalkyl" means a cyclizedalkyl having from four to about nine ring carbon atoms being substitutedwith an alkyl group, preferably a lower alkyl group. The term"haloalkyl" embraces radicals wherein any one or more of the carbonatoms is substituted with one or more halo groups, preferably selectedfrom bromo, chloro and fluoro. Specifically embraced by the term"haloalkyl" are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. Amonohaloalkyl group, for example, may have either a bromo, a chloro, ora fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups maybe substituted with two or more of the same halo groups, or may have acombination of different halo groups. A dihaloalkyl group, for example,may have two bromo atoms, such as a dibromomethyl group, or two chloroatoms, such as a dichloromethyl group, or one bromo atom and one chloroatom, such as bromochloromethyl group. Examples of a polyhaloalkyl aretrifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and2,2,3,3-tetrafluoropropyl groups. The term "aryl" embraces aromaticradicals such as phenyl, biphenyl and naphthyl. The term "aralkyl"embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyland triphenylmethyl. The terms "benzyl" and "phenylmethyl" areinterchangeable. The term "alkoxy" embraces linear or branchedoxy-containing radicals having an alkyl portion of one to about tencarbon atoms, such as methoxy, ethoxy, isopropoxy and butoxy. The term"alkylthio" embraces radicals containing a linear or branched alkylgroup of one to about ten carbon atoms attached to a divalent sulfuratom, such as a methythio group. The terms "aryloxy" and "arylthio"denote, respectively, aryl groups having an oxygen or sulfur atomthrough which the radical is attached to a nucleus, examples of whichare phenoxy and phenylthio. The terms "sulfinyl" and "sulfonyl", whetherused alone or linked to other terms, denote respectively, divalentradicals ##STR11## The term "acyl" whether used alone, or within a termsuch as acyloxy, denotes a radical provided by the residue remainingafter removal of hydroxy from an organic acid, examples of such radicalbeing lower alkanoyl, such as acetyl, and benzoyl. The term "alkenyl"embraces linear or branched radicals having two to about twenty carbonatoms, preferably three to about ten carbon atoms, and containing atleast one carbon-carbon double bond. The term "alkynyl" embraces linearor branched radicals having two to about twenty carbon atoms, preferablytwo to about ten carbon atoms, and containing at least one carbon-carbontriple bond. The terms "cycloalkenyl" and "cycloalkynyl" embrace cyclicradicals having three to about ten ring carbon atoms including,respectively, one or more double or triple bonds involving adjacent ringcarbons. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy group. The "alkoxy" or "alkoxyalkyl"radicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkylgroups. The terms "heteroaryl", "aromatic heterocyclic group" and"fully-unsaturated heterocyclic group" embrace aromatic ring systemscontaining one or two hetero ring atoms selected from oxygen, nitrogenand sulfur in a ring system having five to about ten ring members; suchring system could be monocyclic, bicyclic, or fused ring system. Theterm "heteroaralkyl" embraces heteroaryl groups attached to the nucleusof Formula I through an alkyl group. The term "heterocyclic" embracesgroups which may be saturated or partially unsaturated having three toeight ring members and which heterocyclic ring contains a hetero atomselected from oxygen atom, sulfur atom and NH, examples of which arethienyl, furanyl, pyridinyl and pyrimidyl. The term "heterocyclicalkyl"embraces heterocyclic groups attached to the nucleus of Formula Ithrough an alkyl group.

Within this class of compounds of the invention are the pharmaceuticallyacceptable salts of the compounds of Formula I, including acid additionsalts and base addition salts. The term "pharmaceutically-acceptablesalts" embraces "pharmacologically-acceptable salts" commonly used toform alkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic,phenylacetic, mandelic, embonic (pamoic), methansulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic,toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic,algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid.Suitable pharmaceutically-acceptable base addition salts of compounds ofFormula I include metallic salts made from calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made fromN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound of Formula I by reacting, for example, the appropriate acid orbase with the compound of Formula I.

Based upon the foregoing, the meanings of the following terms should bereadily discernible, namely, "cycloalkyl", "cycloalkylalkyl","phenylalkyl" and "alkoxy".

Compounds of Formula I have been found to inhibit renin and thus limitthe production of angiotensin I which, in turn, limits the production ofangiotensin II in mammals. Angiotensin II is a potent vasoconstrictorand participates in the formation of aldosterone which regulates sodiumand water balance in mammals. Thus, compounds of Formula I aretherapeutically useful in methods for treating hypertension byadministering to a hypertensive patient a therapeutically-effectiveamount of a compound of Formula I. The phrase "hypertensive patient"means, in this context, a mammalian subject suffering from the effectsof hypertension or susceptible to a hypertensive condition if nottreated to prevent or control such hypertension.

These compounds can be formulated into pharmaceutically-acceptabledosage forms by any of a number of well-known carriers or diluents. Thecompounds can be formulated using pharmaceutically-acceptable acidaddition salts which are pharmacologically-acceptable and which can beused in a suitable hydrated form. The formulated compounds can beadministered in oral dosage forms such as tablets, capsules, pills,powders, or granules. The compounds can also be administeredintramuscularly, using forms known to the pharmaceutical art. Ingeneral, the preferred form of administration is oral. A therapeuticallyeffective but non-toxic quantity of the compound is employed intreatment of high blood pressure in mammals. The dosage regimen forpreventing or treating hypertension with the compounds of Formula I isselected upon consideration of a variety of factors, including the type,age, weight, sex, and medical condition of the patient, the severity ofthe hypertension, the route of administration, and the particularcompound employed. Dosages of active compounds are ordinarily in therange from about 0.5 to about 100 mg/kg (active compound-to-bodyweight), and preferably from about 1.0 to about 20 mg/kg given orally orby injection.

Compounds of Formula I are also useful as diagnostic agents foridentification of hypertension due to renin excess.

Compounds of Formula I can be administered as prodrugs. Preferably,esterification of one or more of the hydroxyl groups of the compounds ofFormula I is accomplished with amino acids to make aminoesters,succinates to makes succinic acid esters, alkanoic acids to makecarboxylic acid esters such as valerates, or phosphates to makephosphoric acid esters. Aminoesters and valerates of the Formula Icompounds are more preferred.

Procedures for preparation of compounds of Formula I are set forth inthe following "General Synthetic Scheme" and in the descriptions of thesynthesis of specific compounds described in Examples 1-26 which followthereafter.

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethese compounds. All temperatures expressed are in degrees Centigrade.Within the foregoing synthetic description and examples which follow,abbreviations have meanings as indicated below:

Boc=t-butyloxycarbonyl

i-Bu=isobutyl

Leu=leucine

Ac=acyl

Me=methyl

TFA=trifluoroacetic acid

THF=tetrahydrofuran

im=imidazole

AMBA=alpha-methyl-β-analine (also known as 2-R-methyl-3-aminopropionicacid)

Procedures for preparation of compounds of Formula I are set forth inthe following "General Synthetic Scheme" and in the descriptions of thesynthesis of specific compounds described in Examples 1-26 which followthereafter. The synthesis of renin inhibitory compounds of Formula I maybe summarized as follows: A suitably protected β-amino acid, preferablyprotected with a t-butyloxycarbonyl group for nitrogen, is coupled to asuitably protected aminodiol using a published procedure [F. M. F. Chenet al, J. Org. Chem., 48, 2939 (1983)]. This conjugate is then treatedwith trifluoroacetic acid (or other appropriate agent) to remove the Bocgroup, and this resulting material is neutralized and coupled usingMethods A, B, C or D (described below) to form heterocyclic orhomocyclic carboxylic acid derivatives to produce the renin inhibitorsof this invention. The substituents R¹ through R⁷ represent groups asmentioned above in the general description of compounds within FormulaI. ##STR12##

EXAMPLE 1 N-Boc-α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

To a solution of N-Boc-α-(R,S)-methyl-β-alanine (137 mg, 0.67 mmol) inmethylene chloride (4mL) at -10° C. was added N-methylpiperidine (61 mg,0.61 mmol) followed by isobutylchloroformate (75 mg, 0.55 mmol). Afterstirring for 5 min, a solution of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (101 mg,0.41 mmol) in methylene chloride (2 mL) was added. The resultingsolution was stirred for 3 hours at -10° C., followed by 2 hours at roomtemperature at which time a white solid was isolated by filtration (60mg, 34% yield): Rf=0.3 (5% MeOH/methylene chloride, silica gel); mp197°-200°; 1H NMR (CDCl3): consistent with proposed structure. Anal.calcd for C₂₃ H₄₄ N₂ O₅ +0.25 H₂ O: C, 63.77; H, 10.35; N, 6.46. Found:C, 63.84; H, 10.50; N, 6.45.

EXAMPLE 2 α-(R)-Methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Example 1 (53 mg, 0.12 mmol) was stirred with amixture of trifluoroacetic acid and methanol (9:1, 5 mL). The resultingsolution was allowed to stand at room temperature for 20 minutes, thenthe solvent was evaporated. The resulting oil was stirred for 2 hourswith aqueous potassium carbonate (5%, 10 mL). This mixture was thenextracted with ethyl acetate which was dried, filtered and evaporated togive the title compound (40 mg, 100%): Rf: 0.10 (5% MeOH/methylenechloride, silica gel). This material was used without furtherpurification.

EXAMPLE 3 N-Methyl-N-Boc-α-(R)-methyl-β-alanine

To a solution of N-Boc-α-(R,S)-methyl-β-alanine (1.33g, 6.5 mmol) in THF(80ml)was added pentane washed sodium hydride(1.2g, 60% in oildispersion) followed by methyl iodide (2 ml, exess). The reactionmixture was stirred overnight and then poured into an iced solution ofcitric acid (0.5N). The aqueous THF solution was extracted into ethylacetate. Then the required acid was back extracted between ethylacetate, sodium hydrogen carbonate and potassium hydrogen sulphatesolutions. The organic extracts were dried (MgSO₄) and evaporated toafford the title compound. (1.00 g, 71%), Anal: C₁₀ H₁₉ NO₄.0.3H₂ O,Calc: C, 53.94; H, 8.87; N, 6.29. Found, C, 54.02; H, 8.56; N, 6.63.

EXAMPLE 4 N-Methyl-N-Boc-α-(R)-methyl-β-alanineamide of (2S, 3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

To a solution of N-Methyl-N-Boc-α-(R)-methyl-β-alanine (900 mg, 0.67mmol) in methylene chloride (10 mL) at -10° C. was addedN-methyl-piperidine (500 ul, 4.15 mmol) followed byisobutylchloroformate (450 mg, 3.3 mmol). After stirring for 5 min, asolution of (2S. 3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (655 mg, 2.7mmol) in methylene chloride (4 mL) was added. The resulting solution wasstirred for 5 hours at -10° C. The solvent was evaporated in vacuo toafford an oily residue which was partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic layer was separated and dried(MgSO₄). After evaporation the crude residue was dissolved in methanol(4 mL) to which potassium hydroxide solution (1 mL, 1M) was added. Thereaction mixture was stirred for 30 min, evaporated to dryness and theresidue extracted into ethyl acetate. The organic extracts were washedwith water, citric acid (0.5M) and saturated sodium bicarbonate solutionand dried over MgSO₄. Evaporation of the solvent gave a yellow residuewhich was recrystallized from diethyl ether to afford the title compound(850 mg, 71% yield), Anal: C₂₄ H₄₆ N₂ O₅, Calc, C, 65.12; H, 10.47; N,6.33; Found, C, 65.10; H, 10.37; N, 6.43.

EXAMPLE 5 N-Methyl-α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

The title compound of Example 4 (820 mg, 1.86 mmol) was stirred with amixture of trifluoroacetic acid and methanol (9:1, 5 mL). The resultingsolution was allowed to stand at room temperature for 20 minutes, thenthe solvent was evaporated. The resulting oil was stirred for 2 hourswith aqueous potassium carbonate (5%, 10 mL). This mixture was thenextracted with ethyl acetate which was dried, filtered evaporated andprecipitated from diethyl ethyl to afford the title compound. (580 mg,92%). Anal: C₁₉ H₃₈ N₂ O₃, Calc C, 64.59; H, 11.18; N, 7.93; Found, C,64.59; H, 10.50; N, 7.61.

EXAMPLE 6 ##STR13## N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]benzene-butanamide

To a stirred solution of phenylbutyric acid (60 mg, 0.183 mmol) inmethylene chloride (2 mL) in an ice/salt bath was addedN-methylpiperidine (0.08 mL, 2 eq) followed by isobutylchloroformate (40mg, 1.6 eq). After 5 min, the title compound of Example 2 (60 mg, 0.183mmol) in methylene chloride/methanol (1 ml/0.1 ml) was added and thereaction mixture was stirred at 0° C. for about 15 hours. The solventwas evaporated in vacuo to afford an oily residue which was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organiclayer was separated and dried (MgSO₄). After evaporation the cruderesidue was dissolved in methanol (4 mL) to which potassium hydroxidesolution (1 mL,1M) was added. The reaction mixture was stirred for 30min, evaporated to dryness and the residue extracted into ethyl acetate.The organic extracts were washed with water, citric acid (0.5M) andsaturated sodium bicarbonate solution and dried over MgSO₄. Evaporationof the solvent gave a yellow residue which was re-crystallized fromdiethyl ether to afford the title compound. (38 mg, 44% yield), Anal:C₂₈ H₄₆ N₂ O₄.1.8 H₂ O, Calc, C, 66.32; H, 9.86; N, 5.52. Found, C,66.32; H, 9.18; N,5.57.

EXAMPLE 7 Method B ##STR14##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-2-carboxamide

To a stirred solution of the title compound of Example 2 (150 mg, 0.46mmol) in methylene chloride/methanol (5 ml/0.2 ml) was addedtriethylamine (0.2 ml, excess) followed by indole-2-oyl chloride (160mg, 2 eq) and a catalytic amount of 4-dimethylaminopyridine. Thereaction mixture was stirred at 0° C. for 15 hours. The solvent wasevaporated in vacuo to afford an oily residue which was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organiclayer was separated and dried (MgSO₄). After evaporation the cruderesidue was dissolved in methanol (4 mL) to which potassium hydroxidesolution (1 mL,1M) was added. The reaction mixture was stirred for 30min, evaporated to dryness and the residue extracted into ethyl acetate.The organic extracts were washed with water, citric acid (0.5M) andsaturated sodium bicarbonate solution and dried over MgSO₄. Evaporationof the solvent gave a yellow residue which was recrystallized fromdiethyl ether to afford the title compound. (85mg, 40% yield), Anal: C₂₇H₄₁ N₃ O₄, Calc, C, 68.72; H, 8.76; N, 8.91; Found, C, 68.62; H; 8.63;N, 8.86.

EXAMPLE 8 Method C ##STR15##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]benzofuran-2-carboxamide

To a stirred solution of the title compound of Example 2 (40 mg, 0.122mmol) in methylene chloride/pyridine (1 ml/1 ml) at room temperaturewere added benzofuran-2-carboxylic acid anhydride (74 mg, 2 eq) and acatalytic amount of 4-dimethylaminopyridine. The reaction mixture wasstirred for about 15 hours. The solvent was evaporated in vacuo toafford an oily residue which was partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic layer was separated and dried(MgSO₄). After evaporation the crude residue was dissolved in methanol(4 mL) to which potassium hydroxide solution (1 mL,1M) was added. Thereaction mixture was stirred for 30 min, evaporated to dryness and theresidue extracted into ethyl acetate. The organic extracts were washedwith water, citric acid (0.5M) and saturated sodium bicarbonate solutionand dried over MgSO₄. Evaporation of the solvent gave a yellow residuewhich was recrystallized from diethyl ether to afford the titlecompound. (30 mg, 52% yield), Anal: C₂₇ H.sub. 40 N₂ O₅.1.3 H₂ O, Calc:C, 65.38; H, 8.66; N, 5.65. Found, C, 65.32; H, 8.43; N, 5.55.

EXAMPLE 9 Method D ##STR16##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]1H-indole-2-acetamide

To a stirred solution of the title compound of Example 2 (60 mg, 0.183mmol) a catalytic amount of 4-dimethylaminopyridine and indole-2-aceticacid (32 mg, 1 eq) in DMF (2 ml) was addeddimethylaminopropyl-3-ethylcarbodiimide (35 mg, 1 eq) at 0° C. Thereaction mixture was stirred at room temperature for about 15 hours. Thesolvent was evaporated in vacuo to afford an oily residue which waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic layer was separated and dried (MgSO₄). After evaporation thecrude residue was dissolved in methanol (4 mL) to which potassiumhydroxide solution (1 mL,1M) was added. The reaction mixture was stirredfor 30 min, evaporated to dryness and the residue extracted into ethylacetate. The organic extracts were washed with water, citric acid (0.5M)and saturated sodium bicarbonate solution and dried over MgSO₄.Evaporation of the solvent gave a yellow residue which wasrecrystallized from diethyl ether to afford the title compound. (65 mg,72% yield), Anal: C₂₈ H₄₃ N₃ O₄, Calc, C, 69.25; H, 8.92; N, 8.65;Found, C, 69.17; H, 9.13; N, 8.56.

EXAMPLE 10 Method D ##STR17##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-N-methyl-benzenebutanamide

The title compound of Example 5 was coupled to 4-phenylbutyric acidusing Method A. (56% yield), Anal: C₂₉ H₄₈ N₂ O₄.0.2 H₂ O, Calc, C,70.75; H, 9.91; N, 5.69; Found, C, 70.83; H, 9.72; N, 5.77.

EXAMPLE 11 ##STR18##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]cyclohexane-butanamide

The title compound of example 2 was coupled to 4-cyclohexylbutyric acidusing Method A (58% yield). Anal: C₂₈ H₅₂ N₂ O₄, Calc, C, 69.96; H,10.90; N, 5.83; Found, C, 69.76; H, 10.95; N, 5.79.

EXAMPLE 12 ##STR19##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-N-methyl-cyclohexanebutanamide

The title compound of Example 5 was coupled to 4-cyclohexylbutyric acidusing Method A. (70% yield) Anal: C₂₉ H₅₄ N₂ O₄.0.2 H₂ O, Calc, C,69.89; H, 11.00; N, 5.62; Found, C, 69.97; H. 11.00; N, 5.50.

EXAMPLE 13 ##STR20##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-methoxy-benzenepropanamide

The title compound of Example 2 was coupled to3-(4-methoxyphenylpropionic acid using Method A. (68% yield), Anal: C₂₈H₄₆ N₂ O₅, Calc, C, 68.54; H, 9.45; N, 5.71; Found, C, 68.24,; H, 9.58;N, 5.75.

EXAMPLE 14 ##STR21##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-2-quinaldylamide

27 mg (0.16 mmoles) of quinaldic acid was coupled to 30 mg (0.09 mmoles)of title compound of Example 2 using coupling Method A. Yield: 96%. 200MHz NMR consistent with structure. C: cal'd, 69.54; found, 68.21. H:cal'd, 8.54; found, 8.84. N: cal'd, 8.69; found, 8.23. 95.34% pure byHPLC.

EXAMPLE 15 ##STR22##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-2-quinoxalinecarboxamide

86 mg (0.494 mmoles) of 2-quinoxalinecarboxylic acid was coupled to 101mg (0.307 mmoles) of title compound of Example 2 using coupling MethodA. Yield: 92%. 200 MHz NMR consistent with structure. C: cal'd, 66.92;found, 67.17. H: cal'd, 8.32; found, 8.38. N: cal'd, 11.56; found,11.36.

EXAMPLE 16 ##STR23##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-nalidixylamide

117 mg (0.504 mmoles) of nalidixic acid was coupled to 104 mg (0.317mmoles) of title compound of Example 2 using coupling Method A. Yield:115 mg. 200 MHz NMR consistent with structure. C: cal'd, 66.39; found,65.73. H: cal'd, 8.54; found, 8.48. N: cal'd, 10.32; found, 10.09.91.70% pure by HPLC.

EXAMPLE 17 ##STR24##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-(R,S)-α-methyl-hydrocinnamide

0.487 g (2.97 mmoles) of α-methyl-hydrocinnamic acid was coupled to0.609 g (1.85 mmoles) of title compound of Example 2 using couplingMethod A. Yield: 90 mg. 200 MHz NMR consistent with structure. C: cal'd,70.85; found, 66.63. H: cal'd, 9.77; found, 9.81. N: cal'd, 5.90; found,6.13.

EXAMPLE 18 ##STR25##N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]N-methyl-1H-indole-2-carboxamide

The title compound of Example 5 was coupled to indole-2-carboxylic acidusing Method B. (50%) Anal: C₂₈ H₄₃ N₃ O₄.0.2H₂ O Calc: C, 68.14; H,8.94; N 8.5 g; Found: C, 68.68; H, 8.88; N, 8.97.

EXAMPLE 19 ##STR26##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]2S*-methyl-3-oxopropyl]-5-fluoro-1H-indole-2-carboxamide

The title compound of Example 2 was coupled to5-fluoroindole-2-carboxylic acid using Method A. (68% yield), Anal: C₂₇H₄₀ N₃ O₄ F.1.0 H₂ O, Calc, C, 63.88; H, 8.34; N, 8.28; Found, C, 63.98;H, 7.96; N:8.04.

EXAMPLE 20 ##STR27##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-carboxamide

The title compound of Example 2 was coupled to indole-3-carboxylic acidusing Method B. (58% yield), Anal: C₂₇ H₄₁ N₃ O₄, Calc, C, 68.24;H,.8.78; N, 8.84; Found, C, 68.05; H, 8.26; N, 8.89.

EXAMPLE 21 ##STR28##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-acetamide

The title compound of Example 2 was coupled to indole-3-acetic acidusing Method B.(56% yield), Anal: C₂₈ H₄₃ N₃ O₄ .0.7 H₂ O, Calc, C,67.49; H, 8.98; N, 8.43; Found, C, 67.63; H, 8.96; N, 8.26.

EXAMPLE 22 ##STR29##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-propanamide

The title compound of Example 2 was coupled to indole-3-propionic acidusing method A. (81% yield), Anal: C₂₉ H₄₅ N₃ O₄, Calc, C, 69.71; H,9.08; N, 8.41; Found, C, 69.26; H, 9.13; N, 8.28.

EXAMPLE 23 ##STR30##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-7-chloro-benzofuran-2-carboxamide

The title compound of Example 2 was coupled to7-chlorobenzofuran-2-carboxylic acid using Method A. (38% yield), Anal:C₂₇ H₃₉ N₂ O₅ Cl, Calc,C:63.96, H:7.75, N:5.52, Found, C:64.24, H:8.36,N:5.64.

EXAMPLE 24 ##STR31##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-7-methoxy-benzofuran-2-carboxamide

The title compound of Example 2 was coupled to7-methoxybenzofuran-2-carboxylic acid using Method A(40% yield). Anal:C₂₈ H₄₂ N₂ O₆, Calc, C, 66.91; H, 8.42; N, 5.57; Found, C, 66.45; H,8.34; N, 4.83

EXAMPLE 25 ##STR32##N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-oxo-4H-1-benzopyran-3-carboxamide

The title compound of Example 2 was coupled to chromone-3-carboxylicacid using Method A: (54% yield), Anal: C₂₈ H₄₀ N₂ O₆, Calc, C, 67.18;H, 8.05; N, 5.60; Found, C, 66.82; H, 8.08; N, 5.47.

EXAMPLE 26 ##STR33##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-oxo-4H-1-benzopyran-2-carboxamide

AMBA-diol was coupled to chromone-2-carboxylic acid using Method A (40%yield). Anal: C₂₈ H₄₀ N₂ O₆. 0.8H₂ O, Calc, C, 65.30; H, 8.14; N, 5.44;Found, C, 65.35; H, 7.74; N, 5.41.

BIOLOGICAL EVALUATION

Compounds of Formula I were evaluated as inhibitors of human renin in anin vitro assay. This human renin inhibition test has been previouslydescribed in detail [Papaioannou et al., Clinical and ExperimentalHypertension, A7(9), 1243-1257 (1985)]. Human renin was obtained fromthe National Institute for Biological Standards, London. An incubationmixture was prepared containing in a total volume of 0.25 mL 100 mMTris-acetate buffer at pH 7.4, 25 x 10⁻⁶ Goldblatt units of renin, 0.05mL of plasma from human volunteers taking oral contraceptives, 6.0 mMsodium EDTA, 2.4 mM phenylmethyl sulfonyl fluoride, 1.5 mM8-hydroxyquinoline, 0.% mg/mL BSA, and 0.024 mg/mL neomycin sulfate.This mixture was incubated for two hours at 37° C. in the presence orabsence of renin inhibitors. The produced angiotensin I was determinedby radioimmunoassay (New England Nuclear kit). Test compounds to beassayed were dissolved in DMSO and diluted with 100 mM Tris-acetatebuffer at pH 7.% Containing 0.5% BSA to the appropriate concentrationThe final concentration of organic solvent in the reaction mixture wasless than 1%. Control incubations at 37° C. were used to correct foreffects of organic solvent on renin activity.

    ______________________________________    In Vitro Inhibition Data    Example #     IC.sub.50 Human Renin (nM)    ______________________________________     6             125     7             26    10             115    11             180    12             23% inhibition @ 10.sup.-6 M    13             30% inhibition @ 5 × 10.sup.-7 M    16             450    20             27% inhibition @ 10.sup.-5 M    21             30% inhibition @ 10.sup.-6 M    22             430    23            1800    24            3000    25            1100    26             520    ______________________________________

Administration of compounds within Formula I to humans can be by anytechnique capable of introducing the compounds into the bloodstream of ahuman patient, including oral administration, and by intravenous,intramuscular and subcutaneous injections.

Compounds indicated for prophylactic therapy will preferably beadministered in a daily dose generally in a range from about 0.1 mg toabout 100 mg per kilogram of body weight per day. A more preferreddosage will be a range from about 1 mg to about 100 mg per kilogram ofbody weight. Most preferred is a dosage in a range from about 1 to about50 mg per kilogram of body weight per day. A suitable dose can beadministered, in multiple sub-doses per day. These sub-doses may beadministered in unit dosage forms. Typically, a dose or sub-dose maycontain from about 1 mg to about 100 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 50 mg of active compound per unit dosage form. Most preferred is adosage form containing from about 3 mg to about 25 mg of active compoundper unit dose.

The active compound is usually administered in apharmaceutically-acceptable formulation, although in some acute-caresituations a compound of Formula I may be administered alone. Suchformulations may comprise the active compound together with one or morepharmaceutically-acceptable carriers or diluents. Other therapeuticagents may also be present in the formulation. Apharmaceutically-acceptable carrier or diluent provides an appropriatevehicle for delivery of the active compound without introducingundesirable side effects. Delivery of the active compound in suchformulations may be by various routes including oral, nasal, topical,buccal and sublingual, or by parenteral administration such assubcutaneous, intramuscular, intravenous and intradermal routes.

Formulations for oral administration may be in the form of capsulescontaining the active compound dispersed in a binder such as gelatin orhydroxypropylmethyl cellulose, together with one or more of a lubricant,preservative, surface-active or dispersing agent. Such capsules ortablets may contain controlled-release formulation as may be provided ina dispersion of active compound in hydroxypropylmethyl cellulose.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. Compound of the formula ##STR34## wherein R₁ isselected from heteroaryl and heteroaralkyl groups represented by##STR35## wherein each of Y and Z is independently selected fromhydrido, lower alkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino,dialkylamino, aryl, sulfhydryl and thioalkyl; wherein n is a numberselected from zero through five, inclusive; wherein each of R₂ and R₄ isindependently selected from hydrido and lower alkyl; wherein R₃ isselected from hydrido, alkyl, benzyl, cycloalkyl, cycloalkylalkyl,alkoxyalkyl and alkylthioalkyl; wherein R₅ is selected from cycloalkyl,phenyl, lower alkyl, cycloalkylalkyl and phenyalkyl; wherein R₆ isselected from hydrido, hydroxy, alkoxy, amino, alkylamino, dialkylamino,lower alkyl and cycloalkyl; wherein R₇ is selected from hydrido, alkyl,haloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl andalkyoxycarbonyl; wherein R₆ and R₇ may further be taken together to forma carbocyclic ring consisting of from three to about eight ring members;and wherein any of the foregoing R₁ through R₇ substituents having asubstitutable position may be substituted with one or more groupsselected from alkyl, alkoxy, halo, haloalkyl, alkenyl, alkynyl andcyano; or a pharmaceutically-acceptable salt thereof.
 2. Compound ofclaim 1 wherein each of Y and Z is independently selected from hydrido,lower alkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino,dialkylamino, aryl, sulfhydryl and thioalkyl; wherein n is a numberselected from zero through five, inclusive; wherein each of R₂ and R₄ isindependently selected from hydrido and lower alkyl; wherein R₃ isselected from hydrido, alkyl, alkoxyalkyl and alkylthioalkyl; wherein R₅is selected from substituted or unsubstituted lower alkyl,cycloalkylalkyl and phenyalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino and dialkylamino; wherein R₇ isselected from hydrido, alkyl, haloalkyl, cycloalkylalkyl,alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl; wherein R₆ and R₇may further be taken together to form a carbocyclic ring consisting offrom three to about six members; and wherein any of the foregoing R₁through R₇ substituents having a substitutable position may besubstituted with one or more groups selected from alkyl, alkoxy, halo,haloalkyl, alkenyl, alkynyl and cyano; or a pharmaceutically-acceptablesalt thereof.
 3. Compound of claim 2 wherein each of Y and Z isindependently selected from hydrido, lower alkyl, hydroxy, halo, alkoxy,amino, alkylamino, dialkylamino, aryl, sulfhydryl and thioalkyl; andwherein n is a number selected from zero through four, inclusive;wherein each of R₂ and R₄ is independently selected from hydrido andmethyl; wherein R₃ is selected from hydrido, methyl, ethyl,methoxymethyl and methylthiomethyl; wherein R₅ is selected from benzyl,cyclohexylmethyl, isobutyl and n-butyl; wherein R₆ is selected fromhydrido, hydroxy, methoxy and dialkylamino; wherein R₇ is selected fromisobutyl, ethyl, propyl and benzyl; and wherein R₆ and R₇ may be takentogether to form a carbocyclic ring consisting of from three to aboutsix members; or a pharmaceutically-acceptable salt thereof.
 4. Compoundof claim 3 wherein each of Y and Z is independently selected fromhydrido, chloro, fluoro, methoxy and dimethylamino; and wherein n is anumber selected from zero through four, inclusive; wherein each of R₂and R₄ is independently selected from hydrido and methyl; wherein R₃ isselected from methyl and ethyl; wherein R₅ is cyclohexylmethyl; whereinR₆ is hydroxy; and wherein R₇ is selected from isobutyl and ethyl; or apharmaceutically-acceptable salt thereof.
 5. Compound of claim 4 whichisN-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-amino]-2S*-methyl-3-oxopropyl]-2-quinoxalinecarboxamideor a pharmaceutically-acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a therapeutically-effective amount of arenin-inhibiting compound and a pharmaceutically-acceptable carrier ordiluent, said renin-inhibiting compound selected from a family ofcompounds of the formula ##STR36## wherein R₁ is selected fromheteroaryl and heteroaralkyl groups represented by ##STR37## whereineach of Y and Z is independently selected from hydrido, lower alkyl,hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino, aryl,sulfhydryl and thioalkyl; wherein n is a number selected from zerothrough five, inclusive; wherein each of R₂ and R₄ is independentlyselected from hydrido and lower alkyl; wherein R₃ is selected fromhydrido, alkyl, benzyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl andalkylthioalkyl; wherein R₅ is selected from cycloalkyl, phenyl, loweralkyl, cycloalkylalkyl and phenyalkyl; wherein R₆ is selected fromhydrido, hydroxy, alkoxy, amino, alkylamino, dialkylamino, lower alkyland cycloalkyl; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may further be taken together to form a carbocyclicring consisting of from three to about eight ring members; and whereinany of the foregoing R₁ through R₇ substituents having a substitutableposition may be substituted with one or more groups selected from alkyl,alkoxy, halo, haloalkyl, alkenyl, alkynyl and cyano; or apharmaceutically-acceptable salt thereof.
 7. The composition of claim 6wherein each of Y and Z is independently selected from hydrido, loweralkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino,aryl, sulfhydryl and thioalkyl; wherein n is a number selected from zerothrough five, inclusive; wherein each of R₂ and R₄ is independentlyselected from hydrido and lower alkyl; wherein R₃ is selected fromhydrido, alkyl, alkoxyalkyl and alkylthioalkyl; wherein R₅ is selectedfrom substituted or unsubstituted lower alkyl, cycloalkylalkyl andphenyalkyl; wherein R₆ is selected from hydrido, hydroxy, alkoxy, amino,alkylamino and dialkylamino; wherein R₇ is selected from hydrido, alkyl,haloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl andalkoxycarbonyl; wherein R₆ and R₇ may further be taken together to forma carbocyclic ring consisting of from three to about six members; andwherein any of the foregoing R₁ through R₇ substituents having asubstitutable position may be substituted with one or more groupsselected from alkyl, alkoxy, halo, haloalkyl, alkenyl, alkynyl andcyano; or a pharmaceutically-acceptable salt thereof.
 8. The compositionof claim 7 wherein each of Y and Z is independently selected fromhydrido, lower alkyl, hydroxy, halo, alkoxy, amino, alkylamino,dialkylamino, aryl, sulfhydryl and thioalkyl; and wherein n is a numberselected from zero through four, inclusive; wherein each of R₂ and R₄ isindependently selected from hydrido and methyl; wherein R₃ is selectedfrom hydrido, methyl, ethyl, methoxymethyl and methylthiomethyl; whereinR₅ is selected from benzyl, cyclohexylmethyl, isobutyl and n-butyl;wherein R₆ is selected from hydrido, hydroxy, methoxy and dialkylamino;wherein R₇ is selected from isobutyl, ethyl, propyl and benzyl; andwherein R₆ and R₇ may be taken together to form a carbocyclic ringconsisting of from three to about six members; or apharmaceutically-acceptable salt thereof.
 9. The composition of claim 8wherein each of Y and Z is independently selected from hydrido, chloro,fluoro, methoxy and dimethylamino; and wherein n is a number selectedfrom zero through four, inclusive; wherein each of R₂ and R₄ isindependently selected from hydrido and methyl; wherein R₃ is selectedfrom methyl and ethyl; wherein R₅ is cyclohexylmethyl; wherein R₆ ishydroxy; and wherein R₇ is selected from isobutyl and ethyl; or apharmaceutically-acceptable salt thereof.
 10. The composition of claim 9wherein said renin-inhibiting compound isN-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-amino]-2S*-methyl-3-oxopropyl]-2-quinoxalinecarboxamideor a pharmaceutically-acceptable salt thereof.
 11. A therapeutic methodfor treating hypertension, said method comprising administering to ahypertensive patient a therapeutically-effective amount of a compound ofthe formula ##STR38## wherein R₁ is selected from heteroaryl andheteroaralkyl groups represented by ##STR39## wherein each of Y and Z isindependently selected from hydrido, lower alkyl, hydroxy, halo, alkoxy,carboxy, amino, alkylamino, dialkylamino, aryl, sulfhydryl andthioalkyl; wherein n is a number selected from zero through five,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and lower alkyl; wherein R₃ is selected from hydrido, alkyl,benzyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl and alkylthioalkyl;wherein R₅ is selected from cycloalkyl, phenyl, lower alkyl,cycloalkylalkyl and phenyalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino, dialkylamino, lower alkyl andcycloalkyl; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may further be taken together to form a carbocyclicring consisting of from three to about eight ring members; and whereinany of the foregoing R₁ through R₇ substituents having a substitutableposition may be substituted with one or more groups selected from alkyl,alkoxy, halo, haloalkyl, alkenyl, alkynyl and cyano; or apharmaceutically-acceptable salt thereof.
 12. The method of claim 11wherein each of Y and Z is independently selected from hydrido, loweralkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino,aryl, sulfhydryl and thioalkyl; wherein n is a number selected from zerothrough five, inclusive; wherein each of R₂ and R₄ is independentlyselected from hydrido and lower alkyl; wherein R₃ is selected fromhydrido, alkyl, alkoxyalkyl and alkylthioalkyl; wherein R₅ is selectedfrom substituted or unsubstituted lower alkyl, cycloalkylalkyl andphenyalkyl; wherein R₆ is selected from hydrido, hydroxy, alkoxy, amino,alkylamino and dialkylamino; wherein R₇ is selected from hydrido, alkyl,haloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl andalkoxycarbonyl; wherein R₆ and R₇ may further be taken together to forma carbocyclic ring consisting of from three to about six members; andwherein any of the foregoing R₁ through R₇ substituents having asubstitutable position may be substituted with one or more groupsselected from alkyl, alkoxy, halo, haloalkyl, alkenyl, alkynyl andcyano; or a pharmaceutically-acceptable salt thereof.
 13. The method ofclaim 12 wherein each of Y and Z is independently selected from hydrido,lower alkyl, hydroxy, halo, alkoxy, amino, alkylamino, dialkylamino,aryl, sulfhydryl and thioalkyl; and wherein n is a number selected fromzero through four, inclusive; wherein each of R₂ and R₄ is independentlyselected from hydrido and methyl; wherein R₃ is selected from hydrido,methyl, ethyl, methoxymethyl and methylthiomethyl; wherein R₅ isselected from benzyl, cyclohexylmethyl, isobutyl and n-butyl; wherein R₆is selected from hydrido, hydroxy, methoxy and dialkylamino; wherein R₇is selected from isobutyl, ethyl, propyl and benzyl; and wherein R₆ andR₇ may be taken together to form a carbocyclic ring consisting of fromthree to about six members; or a pharmaceutically-acceptable saltthereof.
 14. The method of claim 13 wherein each of Y and Z isindependently selected from hydrido, chloro, fluoro, methoxy anddimethylamino; and wherein n is a number selected from zero throughfour, inclusive; wherein each of R₂ and R₄ is independently selectedfrom hydrido and methyl; wherein R₃ is selected from methyl and ethyl;wherein R₅ is cyclohexylmethyl; wherein R₆ is hydroxy; and wherein R₇ isselected from isobutyl and ethyl; or a pharmaceutically-acceptable saltthereof.
 15. The method of claim 14 wherein said compound isN-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]-amino]-2S*-methyl-3-oxopropyl]-2-quinoxalinecarboxamideor a pharmaceutically-acceptable salt thereof.